SCOPE OF WORK Despite advances in therapy, breast cancer remains the second leading cause of cancer related deaths in women. As breast cancer cells are genetically unstable and heterogeneous, focusing on the tumor microenvironment (TME) has the potential to identify new therapeutic targets. One important cytokine in the TME for many cancers is the TGF-?1 ligand that binds TGF-? receptors to promote Smad signaling and gene expression. The TGF-? signaling pathway has well established roles in regulating cellular homeostasis, including proliferation, differentiation and apoptosis. During cancer initiation and progression, the TGF-? signaling pathway is disrupted in a cell and context specific manner. In breast cancer, TGF-? suppresses tumor initiation, but in established cancers, promotes cancer progression to increase invasion and metastasis. As such, TGF-? is an attractive cancer therapeutic target. However, targeting the TGF-? signaling pathway directly has not been successful in the clinic partially due to an incomplete understanding of how TGF-??s role changes during cancer progression. To gain insight into factors that may regulate TGF-? signaling in the tumor microenvironment, we performed a proteomic screen of the breast cancer secretome and identified the integrin binding protein ?IGH3 as a protein able to promote TGF-? signaling. CRISPR/Cas9 silencing of ?IGH3 decreases tumor growth and metastasis in a breast cancer model. This decrease in tumor progression was also associated with decreased TGF-? signaling in vivo. We hypothesize that ?IGH3 increases breast cancer progression by promoting TGF-?-induced EMT, migration and invasion, with effects on TGF-? signaling mediated by increasing active TGF-?1 ligand through proteases. To address this hypothesis, we propose two aims. Aim 1: To establish whether ?IGH3 induces TGF-? signaling by increasing the activation of mature TGF-?1 ligand from the latent-TGF? precursor. Aim 2: To determine whether ?IGH3 increases metastasis by promoting TGF-? signaling and TGF-? induced EMT associated migration, invasion and extravasation. Defining the detailed mechanism of how ?IGH3 increases tumorigenesis through TGF-? signaling could potentially lead to a new therapeutic target in breast cancer.